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Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter

¹ Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
² Molecular Biotechnology Center, University of Torino, Torino, Italy

Correspondence: Martina U. Muckenthaler, University of Heidelberg, Department of Pediatric Oncology, Hematology and Immunology, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. Phone: international +0049.6221566923. Fax: international +0049.6221564580. E-mail: martina.muckenthaler{at}med.uni-heidelberg.de

ABSTRACT

Background: Macrophages of the reticuloendothelial system play a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes. Heme oxygenase 1 (HO1) degrades the heme moiety and releases inorganic iron that is stored in ferritin or exported to the plasma via the iron export protein ferroportin (FPN1). In the plasma iron binds to transferrin and is made available for de novo red cell synthesis. The aim of this study was to gain insight into the regulatory mechanisms that control the transcriptional response of FPN1 to hemoglobin in macrophages.

Design and Methods: FPN1 mRNA expression was analyzed in RAW264.7 mouse macrophages in response to hemoglobin, heme, ferric ammonium citrate or protoporphyrin treatment or to siRNA mediated knockdown or overexpression of Btb And Cnc Homology 1 (Bach1) or nuclear accumulation of Nuclear Factor Erythroid 2-like (Nrf2). Analysis of the FPN1 promoter activity using reporter constructs that contain specific truncations of the FPN1 promoter or mutations in a newly identified MARE/ARE element.

Results: We show that FPN1 is transcriptionally co-regulated with HO1 by heme, a degradation product of hemoglobin. The protoporphyrin ring of heme is sufficient to increase FPN1 transcriptional activity while the iron released from the heme moiety controls Fpn1 translation involving the IRE in the 5’untranslated region. Transcription of FPN1 is inhibited by Bach1 and activated by Nrf2 involving a MARE/ARE element located at position -7007/-7016 of the FPN1 promoter.

Conclusions: This finding suggests that heme controls a macrophage iron recycling regulon involving Bach1 and Nrf2 to assure the coordinated degradation of heme by HO1, iron storage and detoxification by ferritin, and iron export by FPN1.